Transannular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Total Synthesis of a Unique Set of Vinblastine Analogues

Abstract

A powerful tandem [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles initiated by a transannular [4+2] cycloaddition is detailed. An impressive four rings, four carbon-carbon bonds, and six stereocenters are set on each site of the newly formed central six-membered ring in a cascade thermal reaction that proceeds at temperatures as low as 80 °C. The resulting cycloadducts provide the basis for the synthesis of unique analogues of vinblastine containing metabolically benign deep-seated cyclic modifications at the C3/C4 centers of the vindoline-derived subunit of the natural product.

Chiral Lewis Acid-Catalyzed Enantioselective Cycloadditions between Indoles and Cyclic Carbonyl Ylides Derived from Diazodiketone or Diazoketoester Derivatives

“…Using a combination of Rh 2 (S-TCPTTL) 4 and the chiral Pybox-Ph 2 −Ho(OTf) 3 complex, the cycloadducts were obtained in a higher yield along with a good diastereoselectivity, but with reduced enantioselectivities (24− 34% ee) for both the exo-and endo-cycloadducts. By contrast, the higher enantioselectivity of the endo-cycloadduct compared with those of entries 8 and 9 and the highest endo-selectivity were observed using a combination of Rh 2 (R-TCPTTL) 4 and the chiral Pybox-Ph 2 −Ho(OTf) 3 complex (entry 10). From these results, the reduced enantioselectivity of the endocycloadduct shown in entry 9 can be attributed to the mismatched combination of the catalysts.…”

“…To evaluate the efficiency of the dual-activation methodology for the asymmetric synthesis of chiral fused indoline derivatives, we investigated the intermolecular asymmetric cycloaddition reactions between N-methylindole derivatives and six-or fivemembered cyclic carbonyl ylides derived from the corresponding diazodiketone or diazoketoester, which have not been examined for the chiral Rh(II)-catalyzed cycloadditions with indole derivatives, 13a under various combinations of achiral/ chiral Rh or achiral Cu catalysts and chiral lanthanoid metal− 2,6-bis(oxazolinyl)pyridine (Pybox) Lewis acids. Our results have revealed that the combination of Rh 2 (OAc) 4 and chiral lanthanoid Pybox Lewis acid provided the highest enantioselectivities along with high diastereoselectivities and yields.…”

“…To determine the influence of the metal catalysts on the yield and selectivity, the cycloadditions were carried out in the presence of a combination of the Pybox-Ph 2 −Lu(OTf) 3 complex with either Rh 2 (piv) 4 , Rh 2 (tfa) 4 , or Cu(acac) 2 (entries 8−10). Although favorable results were not attained, it is interesting to note that both diastereo-and enantioselectivities were affected, during the generation of cyclic carbonyl ylide, by the choice of catalyst; especially, in the case of Cu 2 (acac) (entry 10), the endo-cycloadduct was favored (exo:endo = 34:66), whereas the enantioselectivtiy of the exo-cycloadduct decreased to 21% ee (compared to that of entry 6).…”

“…The rate of the background reaction corresponding to the metal-associated carbonyl ylide or the free carbonyl ylide also could affect the enantioselectivity. When the chiral Rh catalyst Rh 2 (S-TCPTTL) 4 (2 mol %) was employed, in the absence of any Lewis acids, good enantioselectivities (85−94% ee) were observed for both the exo-and endo-cycloadducts (entries 11 and 12), albeit with moderate yields and diastereoselectivities. Under the same chiral Rh-catalyzed conditions, but in the presence of Lu(OTf) 3 (10 mol %), the cycloaddition resulted in an improved yield of the cycloadducts, but with lower enatioselectivities (entry 13).…”

Attempted Diels-Alder Reactions on Vindoline Derivatives

“…The Diels-Alder reaction was applied in the total synthesis of vinblastine analogues [5], in the enantioselective total synthesis of the akuammiline alkaloid (-)-vincorine [6], and the Strychnos alkaloid (+)-minfiensine [7], as well as in the synthesis of some Aspidosperma alkaloids [8]. Rearrangement through a retro Diels-Alder reaction was observed during the investigations of (-)-criocerine [9].…”